Serotonin has been implicated in a number of conditions, disorders and diseases that originate in the central nervous system. These include conditions, disorders and diseases related to mood, cognitive function, sleeping, eating, pain, depression, anxiety, schizophrenia, and other bodily states. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT1-5-HT7) encompassing 14 human subclasses which modulate the effects of the neurotransmitter 5-hydroxytryptamine (5-HT, serotonin). The 5-HT6 receptor is the latest serotonin receptor to be identified by molecular cloning both in rats and in humans. Mol. Pharmacol. 1993, 43, 320-327; J Neurochem, 1996, 66, 47-56. The human 5-HT6 receptor is a 440 amino acid polypeptide with seven transmembrane spanning domains which is consistent with the structure of a G protein-coupled receptor (GPCR). There is about 89% sequence homology between 5-HT6 receptors in human and rat and the relative distribution of 5-HT6 receptor mRNA in the brain also appears to be similar. Together, these observations suggest that the rat is an appropriate model for predicting the pharmacology of 5-HT6 receptor ligands in humans.
The 5-HT6 receptor is primarily present in the central nervous system and is involved in glutamatergic and cholinergic neuronal activity. Curr Drug Targets CNS Neurol Disord, 2004, 3, 59-79. Blocking the function of 5-HT6 receptors has been found to increase acetylcholine (ACh) and glutamate-mediated neurotransmission, and enhance cognitive processes. Several antidepressants and atypical antipsychotics have also been shown to bind to the 5-HT6 receptor with high affinity. This binding may be a contributing factor in the therapeutic profile of these drugs. 5-HT6 receptor activity has also been linked to generalized states of stress and anxiety. Life Sciences, 1998, 62, 1473-1477. Taken together, these studies and observations suggest that compounds with 5-HT6 receptor affinity may be useful for the treatment of various conditions, disorders or diseases related to the central nervous system (CNS) such as cognitive diseases, neurodegenerative diseases, schizophrenia, anxiety, and depression. Other CNS-related conditions, disorders or diseases that may be affected by modulating 5-HT6 receptor activity include sleep/wakefulness disorders as well as nociception, i.e., the neural processes of encoding and processing noxious stimuli.
The 5-HT6 receptor has also been shown to play a role in conditions, disorders or diseases that relate to food ingestion or food intake, such as, for example, anorexia, cachexia, and obesity. See, for example, Drug Discovery Today, 2006, 11, 283-299. The 5-HT6 receptor is also thought to be involved in conditions, disorders or diseases related to the gastrointestinal (GI) tract, such as irritable bowel syndrome and functional bowel disorder.
Given the broad spectrum of physiologic effects that are mediated by serotonin there is a tremendous amount of interest in identifying and developing compounds that affect serotonergic systems, including those conditions, disorders or diseases that are directly or indirectly mediated, effected, controlled, or influenced by the 5-HT6 receptor. Compounds that have affinity for, interact with, stimulate, or inhibit the 5-HT6 receptor are commonly referred to as 5-HT6 ligands.
This application relates to new compounds with affinity for the 5-HT6 receptor, i.e., 5-HT6 ligands, which may be useful as active ingredients in pharmaceutical preparations for the treatment of certain conditions, disorders or diseases related to the central nervous system (CNS) such as memory disorders, anxiety, epilepsy, migraine, panic attacks, depression, bipolar disorder, obsessive compulsive disorders, cognition/cognitive disorders, mild cognitive impairment (MCl), senile dementia, psychosis, schizophrenia, ADHD/ADD; or for the treatment of pain including neuropathic pain and chronic pain; head trauma or injury; or for the treatment of neurodegenerative conditions, disorders or diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis; or for the treatment of conditions, disorders or diseases related to addiction and/or withdrawal from substances such as narcotics, ethanol (alcoholism), nicotine, and/or benzodiazepines; sleep/wakefulness disorders; or for the treatment of gastrointestinal (GI) conditions, disorders or diseases such as irritable bowel syndrome (IBS), functional bowel disorder; or for the treatment of conditions, disorders or diseases related to feeding behaviors or food intake such as anorexia, cachexia, and obesity.
These compounds may also be useful for the improvement of cognition (cognitive enhancement) and/or improvement of memory in otherwise healthy subjects.